Iridoids from Traditional Chinese Medicine for Neuropathic Pain: Therapeutic Potential and Molecular Mechanisms

Wenjun Wang,1,2 Tianlong Liu,3 Yi Ding,4 Xiaolong Liu,1 Ren Qingji,5 Yi Zhang,6 Zhengxiang Zhang1 1Yan’an Medical College, Yan’an University, Yan’an, Shaanxi, People’s Republic of China; 2Department of Traditional Chinese Medicine, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China; 3Department of Clinical Pharmacy, The 940th Hospital of Joint Logistics Support Force of Chinese PLA, Lanzhou, Gansu, People’s Republic of China; 4Department of Pharmacy, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, People’s Republic of China; 5Xizang University of Tibetan Medicine, Lhasa, Xizang, People’s Republic of China; 6State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, People’s Republic of ChinaCorrespondence: Wenjun Wang, Yan’an Medical College, Yan’an University, No. 580 Shengdi Road, Baota District, Yan’an, Shaanxi, People’s Republic of China, Email [email protected] Zhengxiang Zhang, Yan’an Medical College, Yan’an University, No. 580 Shengdi Road, Baota District, Yan’an, Shaanxi, People’s Republic of China, Email [email protected]: Neuropathic pain (NP) affects global public health problem and remains inadequately controlled by existing drugs. A class of plant-derived iridoids, predominantly glycosides found in traditional Chinese medicine like Lamiophlomis rotata (Benth). Kudo, have recently emerged as promising neuroprotective substances. Here we systematically review pre-clinical efficacy and mechanisms of iridoids across various rodent models of NP. The studies selected for inclusion in this review were those that primarily focused on examining the phytochemical properties and the pharmacological mechanisms related to iridoids. Iridoid glycosides including loganin, catalpol, geniposide, gardenoside, shanzhiside methyl ester, 8-O-acetyl-shanzhiside methyl ester, picroside II and aucubin and seco-iridoid glycosides such as morroniside, gentiopicroside and oleuropein consistently reverse mechanical allodynia and thermal hyperalgesia with ED50 values ranging from 5 μg (intrathecal) to 130– 250 mg/kg (oral), without tolerance after repeated dosing. Mechanistically, iridoid glycosides exert anti-neuropathic effects through a multifaceted mechanism involving anti-inflammatory, antioxidant, glial modulatory, neuroprotective, and potentially neurotransmitter-modulating actions. Additionally, compared with gabapentin, duloxetine or tramadol, iridoids achieve equivalent analgesia accompanied by favorable safety indices and ancillary anxiolytic and antidepressant effects. The main translational gap from the absence of chronic-progressive or primate validation studies, as well as the lack of large-scale clinical trials needed to establish their efficacy and safety in human populations. Collectively, plant-derived iridoids represent mechanistically novel, multi-target and safe candidate ingredients for NP, addressing the major unmet need for efficacy and tolerability beyond current standard of care. Future work should integrate high-quality clinical evidence to accelerate the development of iridoid-based therapeutics for NP. Diagram of iridoid glycosides effects on neuropathic pain, including anti-inflammatory and neuronal protection.Central and peripheral neuropathic pain are highlighted with images of plants. Iridoids against neuropathic pain are central to the diagram. Surrounding effects include anti-inflammatory effects, modulation of glial cell activation, anti-oxidant effects, neuronal protection and apoptosis inhibition and modulation of neurotransmitter systems and ion channels. Chemical structures of iridoid glycosides and seco-iridoid glycosides are shown at the top and bottom of the diagram, respectively.Keywords: iridoids, iridoid glycosides, seco-iridoid glycosides, neuropathic pain, mechanism